tbuckley/cabot-search huggingface dataset:
Abstract 1176: Quantitative integration of PIK3CA hotspots and paralogy identifies occult oncogenic mutants in PIK3CD
Authors: Arijh Elzein, Alexander N. Gorelick, Ino de Bruijn, Barry S. Taylor, Aphrothiti J. Hanrahan, David B. Solit
Journal: Cancer Research (2023)

Abstract The majority of somatic variants identified by tumor genomic profiling are low frequency alterations of unknown biologic and clinical significance. To facilitate the systematic identification of likely oncogenic versus benign somatic mutations, there has been a growing interest in harnessing additional computationally amenable metrics such as sequence paralogy. Here, we developed a novel paralogy-directed computational methodology called Enriched Paralogy to identify Occult Cancer Hotspots (EPOCH), which calculates the significance of mutational recurrence at aligned positions in evolutionarily related genes to prioritize likely oncogenic mutations for in depth functional characterization. We validated the utility of EPOCH using sequencing data from a cohort of 52,676 tumor/normal pairs, with a focus on identifying likely oncogenic mutations in the well characterized PIK3CA (p110α) class 1a PI3K isoform and the lesser characterized PIK3CD (p110δ) isoform. p110δ mutants nominated as likely oncogenic by EPOCH induced AKT pathway activation, enhanced anchorage-independent colony formation, and demonstrated allele-specific dependencies on p85 regulatory protein binding. The potency of PI3K inhibitors against p110δ mutants was at best equal to or less than wildtype p110δ. In sum, we present the novel algorithm EPOCH that integrates paralogy to extend the utility of current recurrence-based precision oncology predictions and to automate the functional interpretation of less common mutations. Our work identifies novel oncogenic and targetable p110δ mutants and supports the inclusion of PIK3CD in targeted sequencing panels despite the relative rarity of mutations in this gene. The therapeutic studies herein also provide the rationale for the development and clinical testing of isoform- or mutant-specific p110δ inhibitors for patients with rare, yet druggable, oncogenic p110δ mutations. Citation Format: Arijh Elzein, Alexander N. Gorelick, Ino de Bruijn, Barry S. Taylor, Aphrothiti J. Hanrahan, David B. Solit. Quantitative integration of PIK3CA hotspots and paralogy identifies occult oncogenic mutants in PIK3CD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1176.
Abstract 1532: Next generation IgM antibody based multimeric platform: ePENDY (engineered pentamer body)
Authors: Sungmuk Kang, Hyeonju Kang, Jihye Koo, Yoojin Kim, Suho Park, Inyoung Lee, Jiye Yi, Hong Jai Lee, Yonghyun Cho, Hyunju Hwang, Kyunggi Hyun, Chungmin Lee, Gyongsik Ha
Journal: Cancer Research (2023)

Abstract Among many candidates from the recent diverging research to develop a multivalent platform, IgM has shown potential as a pharmaceutical because of its avidity coming from natural multimeric target binding ability. IgM has a great advantage of naturally forming multimers, however, there are some unfulfilled needs to become a good pharmaceutical platform, such as limited biological activity, short half-life, safety concerns, and difficult purification steps compared to IgG. Here, we developed an antibody platform, ePENDY, by engineering IgM to improve efficacy, safety, and convenience of manufacturing process. ePENDY has a self-assembling decavalent pentameric structure and it is an improved IgM with maximized biological activity as therapeutics by using flexible linkers. In addition, ePENDY was engineered one of the effector functions of antibodies, ADCC, was greatly increased compared to IgG as well as IgM which does not have this function. More importantly, the presence or absence of effector functions can be controlled depending on the MoA (Mode of action) of the target. Serum half-life of ePENDY was significantly increased compared to natural IgM, and ePENDY showed similar PK profiles as the IgG Fc-based molecules through FcRn recycling. Unlike natural IgM, ePENDY does not bind to any IgM receptors, such as pIgR, FcμR, and Fcα/μR, thereby eliminating possible side effects. In addition, it has been confirmed that ePENDY showed a comparable expression level to that of IgG, and since the purification process can also be set up in a process like IgG, thus production of ePENDY can be facilitated. Based on these results, we are researching ePENDY which are applying various therapeutic molecules, such as antibodies, protein ligand-based active molecules and therapeutic cancer vaccines. We expect that our versatile applicable platform, safe and long acting ePENDY, can be a superior tool for the various therapeutic targets. Citation Format: Sungmuk Kang, Hyeonju Kang, Jihye Koo, Yoojin Kim, Suho Park, Inyoung Lee, Jiye Yi, Hong Jai Lee, Yonghyun Cho, Hyunju Hwang, Kyunggi Hyun, Chungmin Lee, Gyongsik Ha. Next generation IgM antibody based multimeric platform: ePENDY (engineered pentamer body) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1532.
Abstract 2678: Combination therapy with cabozantinib and cannabidiol enhances the apoptotic cell death via phosphorylation of<i>TP53</i> regulated by ER-stress in hepatocellular carcinoma
Authors: Youngsic Jeon, Taejung Kim, Hyukjoon Kwon, Jungyeob Ham, Young-Joo Kim
Journal: Cancer Research (2023)

Abstract Cannabidiol (CBD), a primary constituent of hemp and cannabis, has pharmacologically broad properties for a variety of diseases including cancer. Cabozantinib (CBZ), a potent multikinase inhibitor, has been approved for use in patients with advanced hepatocellular carcinoma (HCC). Recently, research is increasing for combination therapy using CBZ for better improved efficacy and safety for the patients. Here, we investigated the effect of the combination therapy with CBZ and CBD in HCC cells. CBD enhances the sensitivity of CBZ against HCC cells by increasing cytotoxicity and apoptosis. Especially, analysis of phospho-kinase array demonstrated that the apoptotic effect of combination treatment with CBZ and CBD was significantly related phosphorylation of TP53 regulated by endoplasmic reticulum stress (ER-stress) compared to other kinases. Inhibition of TP53 expression and ER-stress abolished the apoptotic effect of combination treatment with CBZ and CBD, revealing no expression changes in Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9. On the other hand, we found that the effect of combination treatment with CBZ and CBD was not associated with cannabinoid receptor 1 (CNR1) and CNR2 receptors signaling pathway. Our findings suggest that combination therapy with CBZ and CBD provides enhanced therapeutic efficacy against HCC. Citation Format: Youngsic Jeon, Taejung Kim, Hyukjoon Kwon, Jungyeob Ham, Young-Joo Kim. Combination therapy with cabozantinib and cannabidiol enhances the apoptotic cell death via phosphorylation ofTP53 regulated by ER-stress in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2678.
Abstract 1413: Chromosome arm aneuploidies as genetic vulnerabilities of triple-negative breast cancer
Authors: Rohan Dandage, Michael Schwartz, Lynn Karam, Alain Pacis, Traver Hart, Guillaume Bourque, Morag Park, Elena Kuzmin
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. It has no approved targeted therapies due to the lack of the expression of key biomarkers, namely Estrogen and Progesterone receptors, and HER2 amplification. As a result, TNBC has the worst prognosis compared to other breast cancer subtypes. We previously showed that chromosome 4p (chr4p) loss is recurrent, correlates with poor prognosis, is an early event in tumor evolution, and confers a proliferative advantage. Here, we propose to leverage chr4p loss as a genetic vulnerability of TNBC by identifying its genetic interactions (GIs) with genes whose inactivation leads to synthetic lethality i.e. loss of viability of chr4p copy loss cells, but not of the chr4p copy neutral cells, or suppression i.e., positive GIs. We first classified breast cancer cell lines with TNBC enriched molecular subtype called basal-like, as chr4p copy loss (9) and chr4p copy neutral (7), using copy number data from CCLE. Associated with chr4p copy loss, the differential expression analysis carried out using CCLE data revealed transcriptomic changes that distinctly cluster the chr4p copy loss and chr4p copy neutral cell lines. We then used the publicly available CRISPR-based genome-wide gene inactivation data from the DepMap project and quantified chr4p loss-associated GIs using multiple scoring methods such as drugZ and MAGeCK. In total, we identified ~200 negative and ~70 positive statistically significant GIs involving genes annotated to biological processes such as translation, metabolism, and others. We have prioritized a subset of them for subsequent experimental validation using CRISPR-Cas9-based gene editing in TNBC cancer cell line models. Alongside, using the publicly available drug sensitivity data obtained from the PRISM project, we identified compounds that impair cell growth in a chr4p loss-specific manner, the strongest of which targeted redox balance. Collectively, the set of GIs, the compound sensitivities, and the computational methods we have generated are unique resources for developing precision oncology therapeutic strategies for TNBC, as well as for other cancers harboring chr4p loss. Citation Format: Rohan Dandage, Michael Schwartz, Lynn Karam, Alain Pacis, Traver Hart, Guillaume Bourque, Morag Park, Elena Kuzmin. Chromosome arm aneuploidies as genetic vulnerabilities of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1413.
Abstract 1671: Discovery of ETS-003, a potent and selective YAP/TAZ-TEAD PPI inhibitor with broad anti-tumor activity in Hippo-YAP aberrant cancers
Authors: Jiajun Lu, Ming Gao, Hao He, Lijian Feng, Zhenting Gao, Wenqi Cui, Kun Yang, Jiting Lu, Qiangang Zheng, Jidong Zhu, Xin Guo
Journal: Cancer Research (2023)

Abstract Hippo/YAP is a conserved signaling pathway controlling organ development, tissue regeneration and immune modulation. Cascade of tumor suppressor genes (NF2, LATS1/2) and multiple signals from cellular microenvironment (mechano-transduction) regulate YAP/TAZ phosphorylation and degradation. The stabilized YAP/TAZ translocate from cytoplasm to nucleus, where they bind with TEADs for transcriptional activation. YAP/TAZ regulate numerous genes expression which play central roles in cell proliferation, apoptosis, tumor microenvironment remodeling, and drug resistance, making them appealing targets for cancer treatment. Disruption of YAP/TAZ-TEAD protein-protein interaction (PPI) has been regarded as an effective approach to abolish YAP/TAZ oncogenic activity. Previously we have reported the discovery of YAP/TAZ-TEAD PPI hit compounds bound at the Ω loop site of TEAD1. Here we report that the CADD-guided optimization of the hit compounds has yielded an orally available and potent YAP/TEAD PPI inhibitor ETS-003 with favorable ADME properties and robust anti-tumor efficacy. ETS-003 could potently block YAP/TAZ-TEAD PPI both in vitro and in cells, and disrupt YAP/TAZ genome-wide chromatin binding, resulting in on-target inhibition of YAP transcriptome. ETS-003 exhibited broad anti-proliferative activity in a variety of solid tumor cell lines. In Hippo-YAP dysregulated mesothelioma models, ETS-003 showed profound anti-tumor activity and good PK/PD/efficacy correlation. Moreover, when combined with MAPK pathway inhibitors (Osimertinib, Sotorasib and MRTX1133), ETS-003 could significantly enhance the anti-proliferative activity, suggesting multiple combination opportunities for ETS-003 in clinical investigations. The non-GLP studies of ETS-003 showed favorable safety margin, and warranted further clinical studies of ETS-003 in solid tumors. Citation Format: Jiajun Lu, Ming Gao, Hao He, Lijian Feng, Zhenting Gao, Wenqi Cui, Kun Yang, Jiting Lu, Qiangang Zheng, Jidong Zhu, Xin Guo. Discovery of ETS-003, a potent and selective YAP/TAZ-TEAD PPI inhibitor with broad anti-tumor activity in Hippo-YAP aberrant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1671.
Abstract 23: Development of a biallelic<i>Dicer1</i>mutant mouse strain for studying the pathogenesis of DICER1 syndrome-associated cancer
Authors: Yemin Wang, Shary Chen, Janine Senz, Maxwell Douglas, Shelby Thornton, Yana Moscovitz, C. Blake Gilks, David Huntsman, Gregg Morin
Journal: Cancer Research (2023)

Abstract DICER1 encodes a RNase III enzyme that post-transcriptionally controls gene expression through governing microRNA (miRNA) biogenesis. We and others have demonstrated that somatic mutations of DICER1 at its RNase IIIb domain metal binding sites, impairing its capability to produce mature miRNAs from the 5P strand of miRNA precursors, occur recurrently in a broad spectrum of cancers associated with the DICER1 syndrome that affects children and youths predominantly. The biallelic DICER1 mutations in these cancers challenge the two-hit hypothesis theory of traditional tumour suppressors, but it remains unproven whether these mutations are sufficient to drive tumorigenesis. The lack of biology relevant preclinical models has also hindered the understanding the pathogenesis. Here, we developed a genetically engineered mouse strain that expresses an inducible knockin Dicer1 missense mutation (Dicer1+/fl-D1693N), equivalent to the DICER1 RNase IIIb hotspot mutation D1709N in human cancers. This conditional strain behaves as a null allele due to an aberrant splicing event without Cre-mediated recombination. When crossed with a well-characterized conditional null Dicer1 strain (Dicer1fl/fl), the resulting compound heterozygous strain (Dicer1fl/fl-D1693N), acts as a hemizygous wildtype allele that is converted to a hemizygous missense mutation allele upon Cre-mediated recombination, reflecting the genetic status of DICER1 in DICER1 syndrome-associated cancer. When crossing with the anti-Mullerian hormone receptor 2 (Amhr2) driven cre strain (Amhr2+/cre), the biallelic Dicer1 mutation resulted in infertility in females by impairing the development of oviduct and endometrium and ultimately drove the development of multicystic tubal and intra-uterine tumours. Histologically, these murine tumors resemble human Müllerian adenosarcoma and other DICER1 syndrome-associated sarcomas. Molecular analysis of these murine tumours validated the miRNA biogenesis defects in 5P-miRNA production, uncovered the activation of the myc signaling and identified that loss of let-7 family miRNAs may drive the transcriptomic rewiring and malignant transformation. Thus, this first DICER1 syndrome-associated murine cancer model faithfully recapitulates the biology of human cancer and provides a unique tool for future investigation and therapeutic development. Citation Format: Yemin Wang, Shary Chen, Janine Senz, Maxwell Douglas, Shelby Thornton, Yana Moscovitz, C. Blake Gilks, David Huntsman, Gregg Morin. Development of a biallelicDicer1mutant mouse strain for studying the pathogenesis of DICER1 syndrome-associated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 23.
Abstract 141: Interrogating subclonal mechanisms of immune evasion and immunotherapy resistance in melanoma
Authors: Isabella Church, Charli Gruen, Antonella Sassano, Julio Valencia, Emily Wu, Howard Yang, Gabe Needle, Cari Smith, Sung Chin, Jessica Ebersole, Christina Marcelus, Anyen Fon, Huaitian Liu, Chi-Ping Day, Howard Young, Maxwell Lee, Glenn Merlino, Eva Pérez-Guijarro
Journal: Cancer Research (2023)

Abstract Immune checkpoint blockade (ICB) therapies are the current first-line melanoma treatments within the clinic; however, their specific mechanisms for combatting tumor progression remain unclear and determinants for efficacious and durable responses within patients remain unknown. Intratumor heterogeneity (ITH) provides cancers with significant adaptability, leading to metastatic progression and resistance to treatment, but its complexity often complicates its study. To understand how ITH contributes to ICB response, we derived 24 clonal sublines from single cells of an ICB-sensitive and genetically and phenotypically heterogenous mouse model of melanoma. Genomic and transcriptomic analyses uncovered the diversity of these sublines and their plasticity while in vivo studies demonstrated a wide range of responses to ICB therapy including resistant, partially sensitive, and fully responsive. Distinct responses to anti-CTLA-4 monotherapy compared to combination (anti-CTLA-4 plus anti-PD-L1) therapy were also observed, and further exploration of untreated tumors revealed correlations between highly inflamed and differentiated phenotypes with response to anti-CTLA-4. To better understand changes in plasticity and immune profile throughout the course of treatment, tumors were harvested from the parental cell line prior to treatment and at several timepoints after treatment with anti-CTLA-4 monotherapy. These samples are undergoing high throughput spatial transcriptomics analysis to map the melanoma phenotypes characterized in the clonal sublines with changes in the immune compartment. Furthermore, blood samples were collected to investigate inflammatory profiles of cytokines and chemokines to describe the evolution of the tumor microenvironment throughout the course of immunotherapy. Further studies will allow us to identify predictive and prognostic biomarkers of resistance and relapse upon ICB therapy, respectively. Overall, the 24 clonal sublines serve as a valuable tool to model tumor dynamics associated with ICB efficacy and understand the complex role melanoma plasticity plays in immune evasion mechanisms. Citation Format: Isabella Church, Charli Gruen, Antonella Sassano, Julio Valencia, Emily Wu, Howard Yang, Gabe Needle, Cari Smith, Sung Chin, Jessica Ebersole, Christina Marcelus, Anyen Fon, Huaitian Liu, Chi-Ping Day, Howard Young, Maxwell Lee, Glenn Merlino, Eva Pérez-Guijarro. Interrogating subclonal mechanisms of immune evasion and immunotherapy resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 141.
Abstract 1407: Refining endometrial carcinoma of no-specific molecular subtype by sources of estrogen signaling
Authors: Clarissa Lam, Carol Aghajanian, Nadeem Abu-Rustum, Britta Weigelt, Lora Ellenson, Amir Momeni Boroujeni
Journal: Cancer Research (2023)

Abstract Introduction: Endometrial carcinomas (ECs) of no-specific molecular profile (NSMP-EC) are a large and heterogenous group of tumors. These cancers, in particular endometrioid carcinomas, are thought to be dependent on or benefit from estrogen receptor (ER) signaling. In this study, we sought to determine the sources of ER signaling in patients with NSMP-EC. Methods: We compiled a retrospective database of EC patients who received their primary treatment at our institution from 2014 to 2022, and who had ECs of NSMP based on a surrogate of The Cancer Genome Atlas (TCGA) prognostic EC molecular subtype. We used ovarian volume (binarized using a cutoff of 40 cm3), menopausal status, body mass index (BMI&amp;gt;25), and ESR1 hotspot mutations as surrogate markers for ER signaling. Results: A total of 171 patients with NSMP-EC were included in this study. As expected, menopausal status was correlated with ovarian volume (right ovarian volume median 12.3 cm3 vs 32.8 cm3, p=0.001; left ovarian volume median 10.6 cm3 vs 37.7 cm3, p&amp;lt;0.001). Of these 171 patients, 135 (79%) had an identifiable source of ER signaling. Tumors with ER signaling sources tended to be endometrioid carcinomas (125/135, 93%) whereas a lower proportion of ECs without ER signaling were of endometrioid histology (24/36, 67%; p=0.001). ESR1 hotspot mutations almost exclusively occurred in post-menopausal (11/12 mutated cases) and older patients (median age 69 vs 61 years, p=0.012). PTEN mutations tended to be more frequent in ECs with ER signaling source (70% vs. 50%, P=0.036); in contrast, KRAS hotspot mutations were more common in cases without an identifiable ER source (42% vs. 24%, p=0.067). Additionally, the presence of PTEN mutations was associated with a higher BMI (median 31.1 vs 28.3, p=0.012), whereas FBXW7 mutations were associated with a lower BMI (median 24 vs 30.6, p=0.047). Log-rank survival analysis showed that patients whose ECs lacked an identifiable ER signaling source had a markedly worse survival outcome (p=0.0024). Discussion: We demonstrate that the majority of NSMP-ECs have an identifiable ER signaling source. The minority of NSMP-ECs lacking an ER signaling source may not only represent a hormonally independent tumorigenesis but are also markedly distinct at the molecular, pathologic, and clinical levels. ER protein immunohistochemistry may help in further defining these groups. Citation Format: Clarissa Lam, Carol Aghajanian, Nadeem Abu-Rustum, Britta Weigelt, Lora Ellenson, Amir Momeni Boroujeni. Refining endometrial carcinoma of no-specific molecular subtype by sources of estrogen signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1407.